The adipostat is the mechanism by which the brain detects and maintains constant levels of energy stored in adipocytes in the form of lipids. Key elements of the adipostat include the adipocyte-derived hormone leptin that is expressed in proportion to energy levels and serves to communicate this information to the central nervous system and the central circuits, which sense and respond to leptin. Blockade of one of these circuits, the central melanocortin system, disrupts leptin action, as well as a variety of acute physiological systems involved in energy intake and expenditure, and causes a distinct obesity syndrome in mice and humans, characterized by increased adiposity as well as increased linear growth.
The melanocortin circuitry of the central nervous system (CNS) is a critical component of the adipostat. Srisai et al., Endocrinology, 152(3): 890-902 (2011). Activation of these circuits inhibits food intake and stimulates energy expenditure. The melanocortin-4 receptor (MC4R) is a major component of the machinery controlling food intake and energy expenditure. Consequently, MC4R haploinsufficiency due to mutations in the receptor is responsible for up to 5% of early onset obesity. For this reason, MC4R has been a target of the major pharmaceutical companies for the development of drugs for the treatment of common obesity. The first clinical trials of potent MC4R agonists, however, failed due to pressor activity.
The MC4R, a G-protein coupled receptor (GPCR), couples through Gs and upon agonist binding promotes cAMP production and ERK1/2 mitogen-activated protein kinase phosphorylation. Potent orthosteric agonists can activate GPCR signaling in magnitude and in temporo-spatial patterns that exceed those exhibited under normal physiological patterns of activation. Such orthosteric agonists may thus tend to induce side effects. During the past decade, allosteric modulators have provided a successful alternative to conventional orthosteric agents, albeit for indications other than obesity.